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Breakpoints around the HOXD cluster result in various limb malformations
  1. B Dlugaszewska1,*,
  2. A Silahtaroglu2,*,
  3. C Menzel1,
  4. S Kübart1,
  5. M Cohen3,
  6. S Mundlos1,
  7. Z Tümer2,
  8. K Kjaer2,
  9. U Friedrich4,
  10. H-H Ropers1,
  11. N Tommerup2,
  12. H Neitzel5,
  13. V M Kalscheuer1
  1. 1Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany
  2. 2Wilhelm Johannsen Centre for Functional Genome Research, Department of Medical Biochemistry and Genetics, The Panum Institute, Copenhagen, Denmark
  3. 3Institut für Soziale Pädiatrie und Jugendmedizin der Universität München, Abteilung Genetik, Kinderzentrum München, Munich, Germany
  4. 4Institute of Human Genetics, University of Aarhus, Denmark
  5. 5Institute of Human Genetics, Charité, University Medicine Berlin, Berlin, Germany
  1. Correspondence to:
 Dr Vera Kalscheuer
 Max Planck Institute for Molecular Genetics, Ihnestrasse 73, D-14195 Berlin, Germany; kalscheu{at}


Background: Characterisation of disease associated balanced chromosome rearrangements is a promising starting point in the search for candidate genes and regulatory elements.

Methods: We have identified and investigated three patients with limb abnormalities and breakpoints involving chromosome 2q31. Patient 1 with severe brachydactyly and syndactyly, mental retardation, hypoplasia of the cerebellum, scoliosis, and ectopic anus, carries a balanced t(2;10)(q31.1;q26.3) translocation. Patient 2, with translocation t(2;10)(q31.1;q23.33), has aplasia of the ulna, shortening of the radius, finger anomalies, and scoliosis. Patient 3 carries a pericentric inversion of chromosome 2, inv(2)(p15q31). Her phenotype is characterised by bilateral aplasia of the fibula and the radius, bilateral hypoplasia of the ulna, unossified carpal bones, and hypoplasia and dislocation of both tibiae.

Results: By fluorescence in situ hybridisation, we have mapped the breakpoints to intervals of approximately 170 kb or less. None of the three 2q31 breakpoints, which all mapped close to the HOXD cluster, disrupted any known genes.

Conclusions:Hoxd gene expression in the mouse is regulated by cis-acting DNA elements acting over distances of several hundred kilobases. Moreover, Hoxd genes play an established role in bone development. It is therefore very likely that the three rearrangements disturb normal HOXD gene regulation by position effects.

  • FISH, fluorescence in situ hybridisation
  • SPD, synpolydactyly
  • chromosome rearrangement
  • HOXD
  • limb malformation

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  • * These authors contributed equally to this work

  • Published Online First 24 June 2005

  • This work was supported by a grant from the Deutsche Forschungsgemeinschaft to VK and SM, by the German Human Genome Program (DHGP, grant number 01KW99087), and by the National Genome Research Network (NGFN, project number 01GR0105). AS is supported by the Danish Research Agency. The Wilhelm Johannsen Centre for Functional Genome Research was established by the Danish National Research Foundation.

  • Competing interests: none declared